CN112888698A - 2’-卤代-4’-硫代-2’-脱氧-5-氮杂胞苷类似物及其使用方法 - Google Patents
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- CN112888698A CN112888698A CN201980062607.3A CN201980062607A CN112888698A CN 112888698 A CN112888698 A CN 112888698A CN 201980062607 A CN201980062607 A CN 201980062607A CN 112888698 A CN112888698 A CN 112888698A
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Abstract
本发明描述了5‑氮杂‑2’‑脱氧胞苷的卤代类似物,如5‑氮杂‑4’‑硫代‑2’‑脱氧胞苷(5‑氮杂‑T‑dCyd)的卤代类似物。本发明还描述了包含卤代类似物的药物组合物以及使用卤代类似物抑制瘤形成的方法。在一些示例中,卤代类似物具有式Ia的结构,或其立体异构体、互变异构体或药学上可接受的盐。
Description
相关申请的交叉参考
本申请要求2018年9月25日提交的美国临时专利申请62/736,246的较早申请日的权益,其全部内容通过参考并入本文。
技术领域
本公开涉及5-氮杂-2’-脱氧胞苷的卤代类似物,如5-氮杂-4’-硫代-2’-脱氧胞苷(5-氮杂-T-dCyd)的卤代类似物,以及使用该卤代类似物的方法。
发明内容
在此公开了5-氮杂-2’-脱氧胞苷的卤代类似物和使用该卤代类似物的方法。在一些实施方案中,所述化合物具有式Ia的结构或其立体异构体、互变异构体或药学上可接受的盐:
其中X为卤素;Y为氢、卤素或氘氘;每个R独立地为氢或氘;以及Ra为氢、氘、烷基、烷氧基、氨基或卤素。在某些实施方案中,(i)X为F;或(ii)Y为氢;或(iii)每个R为氢;或(iv)Ra为氢;或(v)上述(i)、(ii)、(iii)和(iv)的任意组合。
在一些实施方案中,该化合物具有式IIa至Va中任意一个或其任意组合的结构:
在任意或所有IIa-Va化合物中,X可以为F,Y可以为H或F,每个R可以为H,和/或Ra可以为H。在某些实施方案中,该化合物为:
一种药物组合物可包含所公开化合物中的至少一者和药学上可接受的载体。在一些实施方案中,该药物组合物被配制为用于静脉给药、口服给药、腹腔给药、皮下给药、直肠给药或含服给药。
一种抑制瘤形成的方法包括使瘤形成细胞与有效量的本文公开的化合物接触。在一些实施方案中,使瘤形成细胞与有效量的化合物接触可减少所述瘤形成细胞的增殖。
在任意或所有实施方案中,使瘤形成细胞与有效量的化合物接触可以包括向患有或疑似患有至少部分以存在癌症等瘤形成细胞为特征的个体施用治疗有效量的化合物。在一些示例中,癌症为肾癌、膀胱癌、乳腺癌、结肠癌、子宫内膜癌、皮肤癌、血液癌、胰腺癌、前列腺癌、骨癌、肝癌、肺癌、食管癌或中枢神经系统癌。在任意或所有实施方案中,向个体施用治疗有效量的化合物可以减少疾病的病症或症状。在一个实施方案中,疾病的病症或症状为实体瘤,向个体施用治疗有效量的化合物可减少实体瘤的生长,减小实体瘤的体积,减少实体瘤的转移或其任意组合。在另一实施方案中,疾病的病症或症状为全血计数异常,向个体施用治疗有效量的化合物可至少部分地使全血计数正常化。在任意或所有实施方案中,施用治疗有效量的化合物可以包括向个体施用包含治疗有效量的化合物的药物组合物。
根据以下参考附图进行的详细描述,本发明的前述和其他目的、特征和优点将变得显而易见。
附图说明
图1为4-氨基-1-((2R,3S,4S,5R)-3-氟-4-羟基-5-(羟甲基)四氢噻吩-2-基)-1,3,5-三嗪-2(1H)-酮(化合物1)的示例性合成方案。
图2为4-烃氧基氧基苯甲硫醇的示例性合成方案。
图3A和3B分别示出化合物1和5-氮杂-T-dCyd对白血病细胞系的GI50(导致净蛋白增加减少50%的药物浓度)数据。
图4A和4B分别示出化合物1和5-氮杂-T-dCyd对中枢神经系统(CNS)癌细胞系的GI50数据。
图5A和5B分别示出化合物1和5-氮杂-T-dCyd对肾癌细胞系的GI50数据。
图6A和6B分别示出化合物1和5-氮杂-T-dCyd对非小细胞肺癌细胞系的GI50数据。
图7A和7B分别示出化合物1和5-氮杂-T-dCyd对黑色素瘤细胞系的GI50数据。
图8A和8B分别示出化合物1和5-氮杂-T-dCyd对前列腺癌细胞系的GI50数据。
图9A和9B分别示出化合物1和5-氮杂-T-dCyd对结肠癌细胞系的GI50数据。
图10A和10B分别示出化合物1和5-氮杂-T-dCyd对卵巢癌细胞系的GI50数据。
图11A和12B分别示出化合物1和5-氮杂-T-dCyd对乳腺癌细胞系的GI50数据。
图12A和12B分别示出小鼠体内随时间变化的HCT-116人结肠癌异种移植瘤体积和小鼠体重,其中小鼠腹腔给药10mg/kg化合物1(F-氮杂-TdCyd)QDx5,静置并重复4个周期;腹腔给药400mg/kg化合物1Q7Dx3;静脉给药240mg/kg F-TdCyd Q7Dx4;腹腔给药1.5mg/kg5-氮杂-T-dCyd QDx5,静置并重复4个周期;或者腹腔给药150mg/kg吉西他滨Q7Dx3。
图13A和13B分别示出小鼠体内随时间变化的BL0382人膀胱癌异种移植瘤体积和小鼠体重,其中小鼠腹腔给药8mg/kg化合物1(F-氮杂-TdCyd)QDx5,静置3个周期;腹腔给药250mg/kg化合物1Q7Dx3;静脉给药200mg/kg F-TdCyd Q7Dx3;腹腔给药1.5mg/kg 5-氮杂-T-dCyd QDx5,静置并重复3个周期;腹腔给药150mg/kg吉西他滨Q7Dx3;或者口服给药8mg/kg化合物1Q7Dx5,静置3个周期。
图14A和14B分别示出小鼠体内随时间变化的OVCAR3人卵巢癌异种移植瘤体积和小鼠体重,其中小鼠腹腔给药8mg/kg化合物1(F-氮杂-TdCyd)QDx5,静置3个周期;腹腔给药250mg/kg化合物1Q7Dx3;静脉给药200mg/kg F-TdCyd Q7Dx3;腹腔给药1.5mg/kg 5-氮杂-T-dCyd QDx5,静置并重复3个周期;腹腔给药150mg/kg吉西他滨Q7Dx3;或者口服给药8mg/kg化合物1Q7Dx5,静置3个周期。
图15A和15B分别示出小鼠体内随时间变化的NCI-H23 NSCLC人肺癌异种移植瘤体积和小鼠体重,其中小鼠腹腔给药10mg/kg化合物1(F-氮杂-TdCyd)QDx5,静置3个周期;口服给药80mg/kg化合物1QDx5,静置3个周期;腹腔给药400mg/kg化合物1Q7Dx3;静脉给药240mg/kg F-TdCyd Q7Dx3;腹腔给药1.5mg/kg 5-氮杂-T-dCyd QDx5,静置3个周期;腹腔给药150mg/kg吉西他滨Q7Dx3。
图16A和16B分别示出小鼠体内随时间变化的HL-60人白血病异种移植瘤体积和小鼠体重,其中小鼠腹腔给药10mg/kg化合物1(F-氮杂-TdCyd)QDx5,静置3个周期;腹腔给药400mg/kg化合物1Q7Dx3;静脉给药240mg/kg F-TdCyd Q7Dx3;腹腔给药1.5mg/kg 5-氮杂-T-dCyd QDx5,静置3个周期;或者腹腔给药150mg/kg吉西他滨Q7Dx3。
具体实施方式
本文公开了5-氮杂-2’-脱氧胞苷的卤代类似物以及使用该卤代类似物的方法。在一些实施方案中,该化合物为5-氮杂-4’-硫代-2’-脱氧胞苷(5-氮杂-T-dCyd)的卤代类似物。所公开化合物可以用于治疗至少部分以存在癌症等瘤形成细胞为特征的疾病。所公开卤代类似物的一些实施方案在治疗某些癌症方面比相应的非卤代氮杂化合物和/或相应的卤代非氮杂类似物更加有效。
I.定义与缩写
为了更好地描述本发明以及在本发明的实践中指导本领域普通技术人员,下面对术语和缩写进行了解释。如本文所用,“包含”意指“包括”,单数形式“一个”或者“一”或者“该”包括复数形式,除非上下文另有明确指出。术语“或者”是指所述替换元素的单个元素或两个以上元素的组合,除非上下文另有明确指出。
除非另有解释,否则本文所用的所有技术和科学术语都具有本领域所属的普通技术人员共同理解的意思。尽管可在实践或本发明的测试中使用与本文所述相似或等同的方法和材料,但是下文描述了适宜的方法和材料。材料、方法和示例仅仅是示意性的,并不旨在限制。根据以下详细描述和权利要求,本发明的其它特征是显而易见的。
除非另有指示,否则说明书或权利要求中使用的所有表达成分、分子量、百分率、温度、时间等的数字均理解为有术语“大约”修饰。因此,除非另有隐含或明确地指示,或者除非上下文能被本领域普通技术人员恰当地理解,从而具有更明确的结构,否则所述数字参数均为近似值,这些近似值依赖于所寻求的期望特性和/或在本领域普通技术人员已知的标准测试条件/方法下的检测极限。当实施方案与现有技术讨论直接且明确地进行区分时,实施方案数目并不是近似值,除非引用了词“大约”。
尽管本文所述的各种成分、参数、操作条件等存在替代方案,但这并不意味着这些替代方案必须是等效的和/或性能相同。除非另有说明,否则也不意味着备选方案按优先顺序列出。
化学中常用术语的定义参见Richard J.Lewis,Sr.(编辑),Hawley's CondensedChemical Dictionary,John Wiley&Sons,Inc.,1997年出版(ISBN 0-471-29205-2)。为了便于审查本发明的各个实施方案,下面对特定术语进行解释。
活性剂:一种药物、药剂、药品、治疗剂、营养制剂或其他化合物,将其施用于个体以产生变化,如疾病或病症或与其有关的至少一种症状的治疗、改善或预防。术语活性剂还包括生物活性剂,如蛋白质、抗体、抗体片段、肽、寡核苷酸、疫苗以及此类材料的各种衍生物。
烷基:具有饱和碳链的烃基。该链可以是环状的、支链的或非支链的。烷基基团的示例包括但不限于甲基、乙基、丙基、丁基、戊基、己基、庚基、辛基、壬基和癸基。
烷氧基:具有结构-OR的基团(或取代基),其中R是取代的或未取代的烷基。甲氧基(-OCH3)是一个示例性烷氧基基团。在取代的烷氧基中,R是被无干扰取代基取代的烷基。
端基差向异构体:一种在环状糖类化合物中出现的差位异构体(只在一个手性碳上具有不同构型的异构体)。
共同给药:术语“共同给药”和“共同施用”是指在大体相同的时间段内将本文公开的化合物与至少一种其他活性剂一起进行给药,但不需要在同一确切时间按时给药(尽管共同给药包括在同一确切时间按时施用)。因此,共同给药可在同一天或不同天进行,或者在相同周或者不同周内进行。
有效量或治疗有效量:足以对个体或给定比例的个体提供有益的或有治疗效果的量。
抑制:如本文所用,术语“抑制”意指减少或预防。
瘤形成/赘生物/赘生的:瘤形成是组织或血液细胞异常生长。异常生长可形成固体块或实体瘤。赘生物可以是良性的,原位的(例如,非侵入性癌或癌前赘生物)或者是恶性的(例如,癌症)。
药学上可接受的载体:本发明中使用的药学上可接受的载体(运载体)是常规的载体。雷明顿:《药学科学与实践》(Remington:The Science and Practice of Pharmacy,TheUniversity of The Sciences in Philadelphia),编辑Lippincott,Williams&Wilkins,Philadelphia,PA,第21版(2005年),描述了适用于对本文所公开的一种或多种菁荧光团进行药物递送的组合物和制剂。
一般来说,载体的性质将取决于所采用的特定给药方式。例如,肠胃外制剂通常包括可注射流体,包括药学上和生物上可接受的流体,如作为运载体的水、生理盐水、平衡盐溶液、葡萄糖水溶液、丙三醇等。在一些示例中,药学上可接受的载体可以是无菌的以适合施用于个体(例如,通过肠胃外注射、肌肉内注射或皮下注射)。除了生物学上中性的载体之外,待施用的药物组合物可包含少量的非毒性辅料,如润湿剂或乳化剂、防腐剂以及pH缓冲剂等,例如,醋酸钠或山梨聚糖单月桂酸酯。
药学上可接受的盐:所公开的菁荧光团的生物相容性盐,所述盐衍生自本领域公知的各种有机和无机反荷离子,并且仅作为示例包括钠、钾、钙、镁、铵、四烷基铵等;并且当所述分子包含基本的功能性时,所述盐为有机或无机酸的盐,例如盐酸盐、氢溴酸盐、酒石酸盐、甲磺酸盐、醋酸盐、马来酸盐、草酸盐等。药学上可接受的酸加成盐是保留游离碱的生物有效性同时由非生物学上或其它不需要的无机酸(如盐酸、氢溴酸、硫酸、硝酸、磷酸等)以及有机酸(如乙酸、三氟乙酸、丙酸、乙醇酸、丙酮酸、草酸、马来酸、丙二酸、丁二酸、富马酸、酒石酸、柠檬酸、苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、对甲苯磺酸、水杨酸)等酸性伙伴形成的那些盐。药学上可接受的碱加成盐包括衍生自无机碱的盐,如钠、钾、锂、铵、钙、镁、铁、锌、铜、锰、铝盐等。示例性盐是铵、钾、钠、钙和镁盐。衍生自药学上可接受的有机无毒性碱的盐包括但不限于伯胺、仲胺及叔胺的盐、包括天然存在的取代胺、环胺及碱性离子交换树脂的取代胺,如异丙胺、三甲胺、二乙胺、三乙胺,三丙胺、乙醇胺、2-二甲氨基乙醇、2-二乙氨基乙醇、二环己胺、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、hydrabamine、胆碱、甜菜碱、乙二胺、葡萄糖胺、甲基葡萄糖胺、可可碱、嘌呤、哌嗪、哌啶、N-乙基哌啶、多胺树脂等。示例性有机碱为异丙胺、二乙胺、乙醇胺、三甲胺、二环己胺、胆碱和咖啡因。(例如,见S.M.Berge等人,“药物盐”,J.Pharm。Sci.,1977;66:1-19,通过引用并入本文。)
立体化学:分子的三维空间结构。
立体异构体:异构体,其分子式和所结合原子的顺序相同但原子在空间中的三维取向不同。
个体:接受治疗、观察或实验的动物或人。
互变异构体:有机化合物的组成异构体,其只在质子和电子的位置上不同,通过氢原子的迁移可相互转换。互变异构体通常在平衡状态下是共存的。
治疗:如本文所用,术语“治疗”意指抑制(减少或发预防)至少一种与一种状况有关的病症或症状,即病症或疾病。对于肿瘤,治疗可以意指减少或预防肿瘤生长,减少肿瘤体积和/或减少或预防肿瘤转移。治疗可以使例如肿瘤的一些或所有临床症状的严重程度降低,使肿瘤的进展减慢(例如,通过延长患有肿瘤的个体的生命),使肿瘤复发的次数减少,使个体的整体健康或幸福得到改善,或者通过本领域公知的对特定病症或疾病有特异性的其它参数。
II.5-氮杂-2’-脱氧胞苷的卤代类似物
5-氮杂-2’-脱氧胞苷的卤代类似物及其立体异构体具有以下通式I的结构:
其中X为卤素(F,Cl,Br或I),Y为氢、卤素(F,Cl,Br或I)或氘,Z为S或O,每个R独立地为氢或氘,以及Ra为氢、氘、烷基(例如,C1-5或C1-3烷基,如甲基、乙基、正丙基或异丙基)、烷氧基、氨基或卤素。在一些实施方案中,Z为S。在任意或所有实施方案中,X可以为F。在任意或所有实施方案中,Y可以为氢或F。在任意或所有实施方案中,每个R可以为氢。在任意或所有实施方案中,Ra可以为氢。
在一些实施方案中,该化合物为5-氮杂-4’-硫代-2’-脱氧胞苷(5-氮杂-T-dCyd)的卤代类似物,具有通式Ia的结构,其中X、Y、R和Ra如上定义:
该卤代类似物可以具有式II~V或其任意组合的立体化学,其中X、Y、R和Ra如上定义:
在一些实施方案中,Z为S,并且该化合物具有式IIa~Va或其任意组合的结构:
在某些实施方案中,该化合物为β-端基异构体,即式II、IIa、III或IIIa的化合物。
示例性化合物包括但不限于:
在一些实施方案中,该化合物为:
在某些实施方案中,该化合物为:
4-氨基-1-((2R,3S,4S,5R)-3-氟-4-羟基-5-(羟甲基)四氢噻吩-2-基)-1,3,5-三嗪-2(1H)-酮
III.药物组合物
本公开还包括包含本文所公开的至少一种化合物的药物组合物。该药物组合物的一些实施方案包括药学上可接受的载体和至少一种化合物。药学上可接受的载体还可包含一种或多种额外的活性成分,如抗癌剂、抗炎剂、抗病毒剂、抗微生物剂、麻醉剂等。用于这些制剂的药学上可接受的载体是常规的载体。例如,雷明顿的《制药科学》,E.W.Martin,Mack Publishing Co.,Easton,PA,第19版(1995年),描述了适用于对本文所公开的化合物进行药物递送的组合物和制剂。
可通过包括肠胃外、口服或直肠途径在内的多种途径向个体施用本文公开的式I化合物。肠胃外途径包括但不限于静脉内、腹腔、皮下、含服和舌下途径。在其他可替换的实施方案中,该化合物可直接暴露于源于个体的细胞、组织或器官中进行离体给药。例如,离体给药可用于确定细胞(例如,癌细胞)是否对所施用化合物有反应。
药物组合物可以是单位计量形式,如可注射流体、口服输送流体(例如,溶液或悬浮液)、鼻腔输送流体(例如,以气雾剂或蒸汽形式输送)、半固体形式(例如,外用乳膏)或固体形式,例如粉末、药丸、片剂或胶囊形式。
一般来说,载体的性质将取决于正在采用的特定给药方式。例如,肠胃外制剂通常包括可注射流体,其包括药学上和生物上可接受的流体,如作为运载体的水、生理盐水、平衡盐溶液、葡萄糖水溶液、丙三醇等。对于固体组合物(例如,粉末、丸剂、片剂或胶囊形式),常规的非毒性固体载体可包括例如药物级别的甘露醇、乳糖、淀粉或硬脂酸镁。除了生物学上中性的载体之外,待施用的药物组合物可包含少量的非毒性辅料,如润湿剂或乳化剂、防腐剂和pH缓冲剂等,例如醋酸钠或山梨聚糖单月桂酸酯。
为了制备药物组合物,所述化合物可与各种药学上可接受的添加剂以及用于分散该化合物的基体或运载体混合。所需的添加剂包括但不限于pH控制剂,如精氨酸、氢氧化钠、甘氨酸、盐酸、柠檬酸等。此外,可包括等渗剂(例如,氯化钠、甘露醇、山梨醇)、吸附抑制剂(例如,80聚乙烯山梨醇酯或812甘油三酯)、溶解度增强剂(例如,环糊精及其衍生物)、稳定剂(例如,血清白蛋白)和还原剂(例如,谷胱甘肽)。组合物还包括佐剂,如氢氧化铝(例如,Amphogel,Wyeth Laboratories,Madison,NJ)、Freund佐剂、MPLTM(3-O-脱酰基单磷酰基脂质A;Corixa,Hamilton,IN)和IL-12(Genetics Institute,Cambridge,MA),以及本领域公知的许多其他合适的佐剂。当该组合物是流体时,一般将制剂的张力(如0.9%(w/v)生理盐水溶液作为单位的张力所测量)调节至在给药部位不会引起实质性的、不可逆的组织损伤的值。一般来说,将溶液的张力调节至大约0.3至大约3.0,如大约0.5至大约2.0或大约0.8至大约1.7。
所述化合物可分散在基体或运载体中,其可包括具有分散所述化合物的能力的亲水性化合物以及任意所需的添加剂。基体可选自宽范围的适宜化合物,这些适宜的化合物包括但不限于多元酸或其盐、羧酸酐(例如,马来酸酐)与其他单体(例如,(甲基)丙烯酸甲基酯、丙烯酸等)的共聚物,诸如聚醋酸乙烯酯、聚乙烯醇、聚乙烯吡咯烷酮的亲水性乙烯基聚合物,诸如羟甲基纤维素、羟丙基纤维素等的纤维素衍生物,以及诸如壳聚糖、胶原、海藻酸钠、明胶、透明质酸等的天然聚合物及其无毒金属盐。通常,选择可生物降解的聚合物作为基体或运载体,例如聚乳酸、聚(乳酸-乙醇酸)共聚物、聚羟基丁酸、聚(羟基丁酸-乙醇酸)共聚物及其混合物。可替代地或另外,可采用诸如聚甘油脂肪酸酯、蔗糖脂肪酸酯等的合成脂肪酸酯作为运载体。可单独或组合使用亲水性聚合物或其他运载体,并且可通过部分结晶化、离子结合、交联等赋予运载体增强的结构整体性。运载体可以是各种形式提供,包括流体或粘性溶液、凝胶、糊剂、粉末、微球和直接应用于粘膜表面的薄膜。
可根据各种方法将化合物与基体或运载体结合,化合物的释放可通过运载体的分散、崩解或相关水通道的形成来实现。在一些情况下,将该化合物分散在由适宜的聚合物例如2-氰基丙烯酸异丁酯制备的微胶囊(微球)或纳米胶囊(纳米球)中(例如,参见Michael等人的《药理学杂志》,43:1-5,1991),然后分散在可生物相容的分散介质中,从而在较长时间内产生持续输送和生物活性。
本发明的组合物可替代地包含作为药学上可接受的运载体的近似生理条件所需的物质,如pH调节剂和缓冲剂、张力调节剂、润湿剂等,例如乙酸钠、乳酸钠、氯化钠、氯化钾,氯化钙、山梨聚糖单月桂酸酯和油酸三乙醇胺。对于固体组合物,可使用常规的无毒的药学上可接受的运载体,其包括例如药物级的甘露醇、乳糖、淀粉、硬脂酸镁、糖精钠、滑石粉、纤维素、葡萄糖、蔗糖、碳酸镁等。
还可将用于施用化合物的药物组合物制备为溶液、微乳液或适用于高浓度活性成分的其他无序结构。运载体可以是溶剂或分散介质,其包括例如水、乙醇、多元醇(例如,甘油、丙二醇、液态聚乙二醇等)及其适宜的混合物。例如,溶液的适当流动性可通过使用卵磷脂等涂层、通过在可分散制剂的情况下保持所需粒径以及通过使用表面活性剂来维持。在许多情况下,希望在组合物中包括等渗剂,例如糖、诸如甘露醇和山梨醇的多元醇或氯化钠。通过在组合物中包括延迟吸收的试剂(例如单硬脂酸盐和明胶)可以实现化合物的长时间吸收。
在某些实施方案中,所述化合物可按时间释放制剂进行施用,例如按包含缓释聚合物的组合物进行施用。这些组合物可以用防止快速释放的运载体(例如控制释放运载体,如聚合物、微胶囊化输送系统或生物粘附凝胶)制备。在所述组合物中包括诸如单硬脂酸铝水凝胶和明胶的延迟吸收的物质,由此可以实现在本发明的各种组合物中的长时间输送。当需要控释制剂时,根据本发明的适于使用的控释粘合剂包括任何生物相容性的控释材料,该材料对活性化合物是惰性的并且能够结合该化合物和/或其它生物活性剂。许多这样的材料在本领域中是已知的。有用的控释粘合剂是在输送后在生理条件下(例如,在粘膜表面或在存在体液的情况下)被缓慢代谢的材料。合适的粘合剂包括但不限于本领域中公知的用于缓释制剂的生物相容性聚合物和共聚物。此类生物相容性化合物对周围组织是无毒且惰性的,且不会引发显著的不良副作用,如鼻刺激、免疫反应、炎症等。它们被代谢成代谢产物,这些代谢产物也具有生物相容性,并且很容易从体内排出。
本发明中使用的示例性聚合物材料包括但不限于衍生自具有可水解酯键的共聚物聚酯和均聚物聚酯的聚合物基质。本领域已知,许多的这些聚合物基质具有可生物降解性并且产生无毒或低毒的降解产物。示例性的聚合物包括聚乙醇酸和聚乳酸、聚(DL-乳酸-共-乙醇酸)、聚(D-乳酸-共-乙醇酸)和聚(L-乳酸-共-乙醇酸)。其他有用的可生物降解或可生物侵蚀的聚合物包括但不限于聚(ε-己内酯)、聚(ε-己内酯-共-乳酸)、聚(ε-己内酯-共-乙醇酸)、聚(β-羟基丁酸)、聚(2-氰基丙烯酸烷基酯)、水凝胶,例如聚(甲基丙烯酸羟乙基酯)、聚酰胺、聚(氨基酸)(例如,L-亮氨酸、谷氨酸、L-天冬氨酸等)、聚(酯-脲),聚(2-羟乙基DL-天冬酰胺)、聚缩醛聚合物、聚正交酯、聚碳酸酯、聚马来酰胺、多糖及其共聚物等聚合物。用于制备此类制剂的许多方法对本领域技术人员来说是公知的(参见,例如,《缓释和控释药物递送系统》,J.R.Robinson主编,Marcel Dekker公司,纽约,1978年)。其他有用的制剂包括控释微胶囊(美国专利4,652,441和4,917,893)、用于制备微胶囊和其他制剂的乳酸-乙醇酸共聚物(美国专利4,677,191和4,728,721)和用于水溶性肽的缓释组合物(美国专利4,675,189)。
本发明的药物组合物一般是无菌的并且在制造、存储和使用的条件下稳定。以所需量将所述化合物加入到含有本文例举的成分中的一种或组合的适宜溶剂中,如果需要,然后过滤杀菌,进而制备得到无菌溶液。一般来说,分散液是通过将该化合物和/或其他生物学活性剂加入到无菌运载体中制备得到的,该无菌运载体包含基础分散介质和所需的来自本文列举的其他成分。在无菌粉末的情况下,制备方法包括真空干燥和冷冻干燥,其产生化合物的粉末加上来自其先前无菌过滤的溶液的任何所需的额外成分。防止微生物发生作用是通过诸如对羟基苯甲酸酯、氯丁醇、苯酚、山梨酸、硫柳汞等的各种抗菌剂和抗真菌剂来实现的。
根据本公开的各种治疗方法,可以与寻求治疗或预防的病症管理相关的常规方法一致的方式将化合物递送至个体中。根据本发明,在足以抑制和/或治疗疾病(例如,癌症)或其一个或多个症状的条件下,向需要此类治疗的个体施用预防或治疗有效量的化合物。
通过口服途径或单次推注递送、经连续递送(例如,连续经皮递送、粘膜递送或静脉递送)延长时间段或以重复的给药方案(例如,通过每小时、每天或每周的重复给药方案)向个体施用该化合物。治疗有效剂量的化合物可以在延长的预防或治疗方案中以重复剂量提供,所述延长的预防或治疗方案会产生具有临床意义的结果以减少与本文所述的靶向状况相关的一个或多个症状或可检测状况。在这种情况下,有效剂量的确定通常以动物模型研究为基础,随后进行人体临床试验,并以显著降低个体靶向疾病症状或状况的发生或严重程度的给药方案为指导。这方面的合适模型包括例如小鼠、大鼠、鸟类、猪、猫、非人灵长类动物和本领域已知的其他可接受的动物模型个体。
IV.使用方法
在一些实施方案中,当瘤形成细胞与有效量的式I化合物或其立体异构体、互变异构体或药学上可接受的盐接触时,所述化合物可抑制瘤形成。抑制瘤形成包括减少与瘤形成有关的病症或症状,如相对于不存在该化合物的情况下的增殖速率,瘤形成细胞的生长速率或增殖速率。当瘤形成是实体瘤时,抑制瘤形成可以减少或预防肿瘤生长,减小肿瘤体积和/或减少实体瘤的转移。
瘤形成可以是良性的,原位/癌前的或恶性的。在一些实施方案中,瘤形成是恶性的-即,癌症-并且使癌细胞与有效量的式I化合物接触可减少或预防癌症细胞的增殖。可通过施用所公开化合物来抑制或治疗的癌症包括但不限于肾癌(肾细胞癌)、膀胱癌、乳腺癌(男性和女性)、结肠癌、子宫内膜癌、肺癌(包括支气管癌)、皮肤癌(包括黑色素瘤)、血液癌(如白血病、淋巴瘤(如非霍奇金淋巴瘤)、骨髓瘤)、胰腺癌、前列腺癌、骨癌、肝癌、肺癌、食管癌和中枢神经系统癌。
可在体内、体外或离体地使瘤形成细胞与式I化合物接触。当确定该化合物对特定瘤形成是否有效时,可在体外(例如,在细胞培养中)或离体(例如,在从个体获得的生物样品中)接触细胞以确定该化合物是否可减少或防止细胞生长和/或增殖。
在一些实施方案中,使瘤形成细胞与有效量的化合物接触包括向患有或疑似患有至少部分以存在癌症等瘤形成细胞为特征的个体施用治疗有效量的化合物。所述个体可以是哺乳动物,如人类或非人类哺乳动物(例如,狗、猫、马、兔子等)。在某些实施方案中,瘤形成细胞是恶性的,疾病是癌症。在任意或所有实施方案中,向个体施用治疗有效量的化合物可减少疾病的病症或症状。在一些实施方案中,病症或症状是实体瘤,向个体施用治疗有效量的化合物可减少实体瘤的生长,减小实体瘤的体积,减少实体瘤的转移或其任意组合。在其他实施方案中,病症或症状可以是全血计数异常,向个体施用治疗有效量的化合物可使全血计数部分地或全部地正常化。至少部分以存在瘤形成细胞为特征的疾病的其它病症或症状包括但不限于咳嗽、气短、咳血、肿胀、疼痛、发热、发冷、频繁感染、皮肤瘙痒或皮疹、食欲不振、恶心、盗汗、持续虚弱、疲劳、气短、腹胀、大便或膀胱习惯改变、便秘、腹泻、血便、直肠出血、黄疸、阴道异常出血、吞咽困难、声音改变、口腔溃疡、口干、流感样症状、头痛、易瘀伤或出血、淋巴结肿大、痣外观改变。
施用治疗有效量的化合物可以包括向个体施用包含治疗有效量的化合物的药物组合物。可以通过包括但不限于静脉、口服、腹腔、皮下、直肠或含服给药的任意适宜途径进行给药。
该化合物的实际剂量会根据个体的疾病适应症和所处的特殊阶段(例如,个体的年龄、大小、健康状况、症状程度、易感因素等)、给药时间和途径、同时正在施用的药物和治疗以及用于激发个体所需活性或生物反应的药剂的特定药理学而变化。剂量方案可以进行调节,以提供最适的预防和治疗应答。治疗有效量也是其中化合物的任何毒性或有害副作用在临床上被治疗有益作用所抵消的量。
可替换地,有效剂量可采用体外模型来确定。使用这样的模型,只需要普通的计算和调整就可以确定适当的浓度和剂量以施用治疗有效量的化合物(例如,有效地引起期望的免疫应答或减少靶向疾病的一个或多个症状的量)。在可替换的实施方案中,如本文所述,出于用于治疗或诊断目的,有效量或有效剂量的化合物可简单地抑制或增强与疾病或症状有关的一种或多种选定的生物活性。
在本发明方法和制剂中的治疗有效量的式I化合物的非限制性范围为成年人0.0001克~100克,如0.001克~50克、0.01克~25克或0.1克~10克。在一些实施方案中,治疗有效量的范围为0.001mg/kg体重~100mg/kg体重,如0.01mg/kg体重~20mg/kg体重、0.01mg/kg体重~10mg/kg体重、0.05mg/kg体重~5mg/kg体重或0.1mg/kg体重~2mg/kg体重。治疗有效量可以单剂量施用或随时间分成两个或更多个剂量。在一些实施方案中,可以每天一次或三次的给药方案向所述个体施用治疗有效量的化合物或包含所述化合物的药物组合物。给药方案可包括1~14天的给药假期。
剂量可由主治临床医生进行更改以在靶部位(例如,体循环)维持所需浓度。可基于口服递送与静脉或皮下给药等递送模式选择较高或较低的浓度。剂量还可基于口服缓释与注射微粒或直肠栓剂等所施用制剂的释放速率来调节。
在一些实施方案中,第二活性剂可以与所述化合物共同施用。可以在单一组合物中单独地或一起施用所述化合物和第二活性剂。可以通过相同途径或不同途径施用第二活性剂。可同时或在不同时间施用所述化合物和第二活性剂。不同的给药可以任意顺序进行。如果是同时施用,则所述化合物和第二活性剂可组合在单一的药物组合物中或者可以作为两种药物组合物同时施用。例如,第二活性剂可以是抗癌剂、抗炎剂、抗微生物剂、抗病毒剂、麻醉剂等。
示意性的抗癌剂包括但不限于阿比特龙、放线菌素D、阿他瑞明、阿米福汀、阿那曲唑、天冬酰胺酶、贝沙罗汀、比卡鲁胺、博莱霉素、白霉素、白消安、卡铂、卡莫司汀、氯霉素、顺铂、克拉屈滨、氯膦酸盐、康美司他丁A4、环磷酰胺、环丙孕酮、阿糖胞苷、达卡巴嗪、柔红霉素、地高辛、己烯雌酚、多西紫杉醇、阿霉素、杜卡霉素DM、表阿霉素、炔雌二醇、依托泊苷、依西美坦、5-氟尿嘧啶、氟达拉滨、氟他胺、叶酸、氟维斯特兰特、吉西他滨、戈舍瑞林、伊班膦酸、依达比星、异环磷酰胺、伊立替康、兰瑞肽、来那度胺、来曲唑、亮丙瑞林、甲羟孕酮、甲地孕酮、美法仑、美司钠、甲氨蝶呤、奥曲肽、帕米膦酸盐、培美曲塞、米托霉素、米托烷、米托蒽醌、奥沙利铂、紫杉醇、戊他汀、匹布罗曼、折叠霉素、丙卡巴嗪、雷帝曲塞、己烯雌酚、链脲佐菌素、他莫昔芬、替莫唑胺、替尼泊苷、拓扑替康、曲普瑞林、长春花碱、长春新碱、长春瑞滨和唑仑膦酸。
V.实施例
实施例1
合成4-氨基-1-((2R,3S,4S,5R)-3-氟-4-羟基-5-(羟甲基)四氢噻吩-2-基)-1,3,5-三嗪-2(1H)-酮
图1为4-氨基-1-((2R,3S,4S,5R)-3-氟-4-羟基-5-(羟甲基)四氢噻吩-2-基)-1,3,5-三嗪-2(1H)-酮(化合物1)的示例性合成方案(方案1)。图2为前体4-烃氧基氧基苯甲硫醇的示例性合成方案(方案2)。
4-辛氧基苯基甲醇(13)
制备:将4-羟基苯甲醛(998.0g,8.17mol)、1-溴辛烷(1664.2g,8.617mol)和碳酸钾(1164.2g,8.436mol)在乙腈(8.0L)中的混合物回流过夜并冷却至环境温度。过滤掉固体,减压浓缩滤液,得到1959.0g(102.3%)粗4-辛氧基苯甲醛。将产物溶解在甲醇(6.0L)中,并将硼氢化钠(100.0g,2.64mol)部分添加到形成的溶液中,同时保持温度低于15℃。在环境温度下将反应混合物搅拌1h。添加氢氧化钠(33.3g,832.5mmol)水溶液(500mL),然后添加乙酸乙酯(3.0L)和盐水(3.0L)。分离有机溶液,用硫酸钠干燥,减压蒸发。向残渣中添加庚烷(2L),并将形成的混合物冷却至4℃。过滤所得固体,用冰冷却的庚烷洗涤并在真空中干燥,得到1715.0g(88.8%)粗4-辛氧基苯基甲醇(13),其在下一步骤中使用,无需进一步纯化。
1H NMR(300MHz,CDCl3/TMS)d 7.26(d,J=8.7Hz,2H);6.87(d,J=8.7Hz,2H);4.59(s,2H);3.95(t,J=6.6Hz,2H);1.73-1.81(m,3H);1.30-1.48(m,10H);0.89(t,J=6.9Hz,3H)ppm
4-辛氧基苯基甲硫醇(14)
制备:将4-辛氧基苯基甲醇(13)(1716.2g,7.26mol)、浓HCl(1345mL,16.41mol)和乙腈(3.8L)的混合物在环境温度下搅拌过夜。然后,添加硫脲(663.8g,8.72mol)和乙腈(1.3L)。将混合物加热至回流2h,冷却至室温并保持过夜。添加氢氧化钠(12162.7g,29.07mol)水溶液(2.3L)。将混合物加热至回流3h并冷却至10℃。在保持温度低于15℃的同时添加浓HCl(1.34L)。混合物用甲基叔丁基醚(7L)萃取。提取物经硫酸镁干燥,减压浓缩。向残渣中加入庚烷(2.2L),蒸发混合物。再次向残留物中添加庚烷(3.4L)。形成的乳状液保存过夜,并通过硅胶垫(1.0kg)过滤。蒸发滤液得到1636.0g(89.3%)4-辛氧基苯基甲硫醇(14)。
1H NMR(300MHz,CDCl3/TMS)d 7.23(d,J=8Hz,2H);6.83(d,J=8Hz,2H);3.95(m,2H);3.72(d,J=7.5Hz,2H);1.75(m,3H);1.25(m,9H);0.87(m,3H)ppm
((2R,3R,4S,5S)-3-(苯甲酰氧基)-4-氟-5-羟基四氢呋喃-2-基)甲基苯甲酸酯(3)
制备:在氮气下,在3000mL单颈圆底烧瓶中,向(2R,3S,4R,5R)-5-((苯甲酰氧基)甲基)-3-氟四氢呋喃-2,4-二基二苯甲酸酯(2)(176g,379mmol)在二氯甲烷(600mL)中的溶液添加乙酸(131mL,796mmol)中的33%氢溴酸,并在室温下搅拌反应6小时。将溶液倒入1200mL饱和碳酸氢钠、固体碳酸氢钠(121g,1440mmol)和1200mL二氯甲烷在0℃下剧烈搅拌的混合物中。分离各层并用1x100mL饱和碳酸氢钠洗涤有机层,用无水硫酸镁上干燥,并在真空中浓缩,得到136g(84%)中间溴,为浅黄色油。1H NMR(400MHz,氯仿-d)δ8.14–7.99(m,3H),7.66–7.45(m,2H),7.50–7.43(m,1H),7.48–7.37(m,1H),6.62(m,1H),5.59–5.47(m,1H),4.87–4.64(m,2H)ppm
在3000mL单颈圆底烧瓶中,在环境气氛下,将粗溴溶解于DMF(600mL)中。用三乙胺(317ml,2274mmol)和水(205ml,1.14E+04mmol)处理溶液,并在室温下搅拌反应。在加入水/三乙胺混合物后,反应从23℃到37℃温升。将搅拌反应1h,然后用2400mL乙酸乙酯稀释。在用1200mL 50%饱和氯化钠剧烈搅拌后,分离各层,并用3x500mL 50%饱和氯化钠洗涤有机层。有机层通过无水硫酸镁过滤,滤液在真空中浓缩,得到116克(85%)标题化合物(3),为粘稠琥珀色油。它被选为直接使用原油,无需进一步净化。
1H NMR(400MHz,氯仿-d)δ8.07–8.02(m,1H),8.06–7.99(m,2H),8.04–7.91(m,1H),7.63–7.28(m,6H),5.66(dd,J=10.4,0.9Hz,1H),5.46(ddd,J=22.3,4.5,1.0Hz,1H),5.21–5.06(m,1H),4.78–4.54(m,4H)ppm
(2R,3R,4)-4-氟-2-羟基-5,5-双((4-(辛氧基)苄基)硫代)戊烷-1,3-二基二苯甲酸酯(4)
制备:将500mL二氯甲烷中的((2R,3R,4S,5S)-3-(苯甲酰氧基)-4-氟-5-羟基四氢呋喃-2-基)甲基苯甲酸酯(3)(58g,161mmol)和(4-(辛酰氧基)苯基)甲硫醇(102g,402mmol)(14)在氮气下装入2000mL单颈圆底烧瓶中。将溶液冷却至0℃并50mL二氯甲烷中的三氟化硼二乙醚(39.7mL,322mmol)逐滴处理。反应物在0℃下搅拌1.5h,并迅速滴加至碳酸钾在600mL分层有200mL二氯甲烷的水中的冰冷却溶液中。混合物通过celite 503过滤,并分离各层。有机层在无水硫酸镁上干燥,滤液在真空中浓缩成琥珀色油。所述油用己烷稀释,装入125GRf柱(Teledyne ISCO)上,并通过340G UltraSil SNAP筒(Biotage,Charlotte,NC)和0-20%乙酸乙酯/己烷梯度在系统上洗脱成多个27mL馏分。将馏分28-100合并并浓缩,得到85g(62%)标题化合物(4),为金黄色油。
1H NMR(400MHz,氯仿-d):δ8.03–7.93(m,2H),7.94–7.86(m,2H),7.61–7.49(m,2H),7.40(m,4H),7.19–7.10(m,2H),6.97–6.88(m,2H),6.71–6.62(m,2H),6.57–6.48(m,2H),5.65(ddd,J=26.9,7.7,1.7Hz,1H),5.01(ddd,J=45.2,9.1,1.8Hz,1H),4.45(dd,J=11.7,2.9Hz,1H),4.34–4.17(m,2H),3.97–3.62(m,8H),2.73(d,J=6.2Hz,1H),1.80–1.65(m,4H),1.49–1.32(m,4H),1.37–1.20(m,17H),0.92–0.81(m,6H)
(2S,3R,4S)-2-(2-氯乙酰氧基)-4-氟-5,5-双((4-(辛氧基)苄基)硫代)戊烷-1,3-二基二苯甲酸酯(5)
制备:将三苯基膦(38.7g,148mmol)和340mL无水THF在氮气下装入1000mL烘箱干燥的三颈圆底烧瓶中。将溶液冷却至-15℃,并用存在于在甲苯(67.2mL,148mmol)中的40wt%偶氮二甲酸二乙酯逐滴处理。混合物搅拌1h,因为其随沉淀物而变得沉重。用存在于在60mL无水THF中的(2R,3R,4)-4-氟-2-羟基-5,5-双((4-(辛氧基)苄基)硫代)戊烷-1,3-二基二苯甲酸酯(4)(25g,29.5mmol)快速逐滴处理浆液。所得悬浮液用100mL存在于无水THF中的氯乙酸(13.94g,148mmol)逐滴处理。反应变得短暂均匀,然后以白色固体的形式沉淀出来。当冷却浴终止时,反应搅拌过夜。在真空中除去挥发物,得到浅黄色糊状物。用900mL 2:1己烷/tBuOMe(甲基叔丁基醚)将糊状物打浆,并通过过滤去除不溶性物质。滤液在真空中浓缩,得到48g粗黄色油。用少量二氯甲烷将粗物质溶解在己烷中,装入100GUltraSil SNAP筒中,并在系统上用0-20%乙酸乙酯/己烷梯度在120G球形筒(Biotage,Charlotte,NC)上洗脱。将馏分4-21合并并浓缩,得到21.70g(80%)标题化合物(5),为黄色油。
1H NMR(400MHz,氯仿-d)δ8.02–7.86(m,4H),7.63–7.49(m,2H),7.48–7.33(m,4H),7.19–7.11(m,2H),6.97–6.86(m,2H),6.70–6.60(m,2H),6.63–6.52(m,2H),5.92(ddd,J=25.5,6.2,2.4Hz,1H),5.54(td,J=6.3,3.2Hz,1H),4.78(ddd,J=46.0,8.5,2.5Hz,1H),4.61–4.44(m,2H),4.37(ddd,J=12.5,6.3,1.2Hz,1H),4.02–3.64(m,10H),1.81–1.66(m,4H),1.49–1.36(m,4H),1.41–1.20(m,16H),0.99–0.80(m,6H)
(2S,3R,4S)-4-氟-2-羟基-5,5-双((4-(辛氧基)苄基)硫代)戊烷-1,3-二基二苯甲酸酯(6)
制备:将(2S,3R,4S)-2-(2-氯乙酰氧基)-4-氟-5,5-双((4-(辛氧基)苄基)硫代)戊烷-1,3-二基二苯甲酸酯(5)(21.70g,23.49mmol)、二氯甲烷(205mL)和甲醇(240mL)在室温、氮气下装入1000mL单颈圆底烧瓶中。用硫脲(17.88g,235mmol)处理黄色溶液,使黄色混合物随着悬浮液变稀然后变重而迅速脱色。用存在于35mL二氯甲烷中的2,6-二甲基吡啶(2.74mL,23.49mmol)逐滴处理悬浮液。重悬浮液在加入二甲基吡啶后15分钟内逐渐接近均匀。在室温下搅拌过夜,共搅拌23小时。用柠檬酸(4.51g,23.49mmol)中和反应,用水(52mL)稀释混合物,并分离各层。用1x250mL 1:1 15%柠檬酸水溶液和饱和氯化钠清洗有机层。将各层分离,并将有机层在无水硫酸镁上干燥,并在真空中浓缩,得到21g浅色糊状物。将残余物的有机成分溶解在1:3二氯甲烷/己烷中,装入100G UltraSil SNAP筒中,并在系统上通过120G球形筒(具有0-20%乙酸乙酯/己烷梯度)洗脱成多个27mL馏分。将馏分24-54合并并浓缩,得到16.98g(85%)标题化合物(6),为浅色油。
1H NMR(400MHz,氯仿-d)δ8.03–7.92(m,4H),7.60–7.49(m,2H),7.45–7.34(m,4H),7.12–6.98(m,4H),6.74–6.59(m,4H),5.72(m,1H),5.02(ddd,J=46.6,6.3,4.4Hz,1H),4.40–4.28(m,2H),3.94(m,1H),3.89–3.67(m,8H),2.64(d,J=6.4Hz,1H),1.71(m,4H),1.49–1.38(m,4H),1.41–1.20(m,18H),0.99–0.80(m,6H)
(2S,3R,4S)-4-氟-2-((甲磺酰基)氧基)-5,5-双((4-(辛氧基)苄基)硫代)戊烷-1,3-二基二苯甲酸酯(7)
制备:将(2S,3R,4S)-4-氟-2-羟基-5,5-双((4-(辛氧基)苄基)硫代)戊烷-1,3-二基二苯甲酸酯(6)(16.95g,20.01mmol)和二氯甲烷(200mL)在氮气下装入1000mL单颈圆底烧瓶中。将溶液冷却至0℃,用存在于20mL二氯甲烷中的甲磺酰氯(2.03mL,26.0mmol)处理,然后滴加存在于20mL二氯甲烷中的三乙胺(3.63mL,26.0mmol)。随着冷却浴的终止时,反应搅拌72小时。用1x100mL水、1x100mL饱和碳酸氢钠和1x100mL 1:1饱和氯化钠/15%柠檬酸水溶液依次洗涤混合物。有机层在无水硫酸镁上干燥,并在真空中浓缩,得到17.99g(97%)的标题化合物,为粘稠琥珀油。使用材料,无需进一步纯化。
1H NMR(400MHz,氯仿-d)δ7.99(m,4H),7.70–7.49(m,2H),7.49–7.35(m,4H),7.21–7.10(m,2H),7.01–6.85(m,2H),6.77–6.64(m,2H),6.62–6.50(m,2H),5.92(m,1H),5.22–5.14(m,1H),4.85(m,1H),4.68–4.56(m,1H),4.44(m,1H),3.93–3.62(m,10H),2.93(s,3H),1.72(h,J=6.8Hz,4H),1.50–1.18(m,19H),0.98–0.84(m,6H).19F NMR(376MHz,氯仿-d)δ-188.51(ddd,J=45.7,25.7,11.3Hz)
((R,3S,4S)-3-(苯甲酸基)-4-氟-5-((4-(辛氧基)苯基)硫代)四氢噻吩-2-基)甲基苯甲酸酯(8)
制备:将(2S,3R,4S)-4-氟-2-((甲磺酰基)氧基)-5,5-双((4-(辛氧基)苄基)硫代)戊烷-1,3-二基二苯甲酸酯(7)(59g,63.8mmol)、无水乙腈(1000mL)、三乙胺(17.78mL,128mmol)和四丁基碘化铵(47.1g,128mmol)在氮气下装入3000mL三颈圆底烧瓶中。将反应混合物加热至回流96小时。使反应冷却至室温,然后将混合物倒入400mL硅胶(230-400目)中并浓缩至干燥。在340G UltraSil SNAP卡式瓶上对塞子进行色谱分析,在系统上用0-15%乙酸乙酯/己烷梯度洗脱。将馏分28-69合并并浓缩得到27.6g(71%)的标题化合物(8),为粘性油,其在真空下结晶得到奶油状彩色固体。19F-NMR显示15:1C-1α/β混合物。
1H NMR(400MHz,氯仿-d)δ8.02–7.90(m,3H),7.65–7.47(m,2H),7.47–7.33(m,4H),7.29–7.19(m,3H),6.86–6.76(m,2H),5.97(ddd,J=9.9,5.0,3.9Hz,1H),5.15(dt,J=50.5,4.7Hz,1H),4.69–4.42(m,3H),3.97–3.82(m,4H),3.80–3.69(m,1H),1.75(m,2H),1.50–1.19(m,10H),0.95–0.82(m,3H).19F NMR(376MHz,氯仿-d)-187.14(ddd,J=50.5,16.6,9.9Hz)
(2R,3S,4S)-4-氟-2-(羟甲基)-5-((4-(辛氧基)苄基)硫代)四氢噻吩-3-醇(9)
制备:将甲醇(MeOH)中的7M氨(187mL,1310mmol)添加到二氯甲烷(50mL)中的((R,3S,4S)-3-(苯甲酸基)-4-氟-5-((4-(辛氧基)苯基)硫代)四氢噻吩-2-基)甲基苯甲酸酯(8)(10g,16.37mmol)溶液中,16.37mmol),并在室温下搅拌所得混合物。在室温下搅拌65h后,在真空中去除挥发物以获得糊状固体。在室温下用己烷(60mL)搅拌固体1h。收集细白色固体,用己烷洗涤,并在过滤器上干燥,获得6.60g(100%)标题化合物(9),为白色固体。
1H NMR(400MHz,DMSO-d6)δ7.24–7.16(m,2H),6.90–6.81(m,2H),5.68(d,J=5.1Hz,1H),5.00(t,J=5.5Hz,1H),4.85(dt,J=51.4,4.9Hz,1H),4.49(dd,J=16.1,4.5Hz,1H),4.20(m,1H),3.92(t,J=6.5Hz,2H),3.91–3.75(m,2H),3.68(m,1H),3.40–3.28(m,1H),3.09(dddd,J=7.6,6.1,4.7,0.9Hz,1H),1.68(m,2H),1.46–1.33(m,2H),1.28(m,8H),0.90–0.82(m,3H).
13C NMR(101MHz,DMSO-d6)δ158.15,131.59,130.42,129.75,128.59,127.86,114.79,99.37,97.49,75.29,75.06,67.81,64.27,64.25,53.22,53.19,50.32,50.13,36.00,35.97,31.67,29.18,29.13,29.10,25.97,22.51,14.38.
19F-NMR(400MHz,DMSO-d6)δ-186.62(dddd,1F)
(3S,4S,5R)-3-氟-4-羟基-5-(羟甲基)四氢噻吩-2-基乙酸酯(10)
制备:将(2R,3S,4S)-4-氟-2-(羟甲基)-5-((4-(辛氧基)苄基)硫代)四氢噻吩-3-醇(37.5g,93mmol)和乙酸(225mL,3972mmol)在氮气下装入500mL单颈圆底烧瓶中。用单份二乙酰氧基汞(44.5g,140mmol)处理无色液体悬浮液,并在室温下将反应混合物搅拌24h。用800毫升庚烷稀释混合物,过滤除去不溶性物质。用300ml二氯甲烷(DCM)洗涤滤饼,然后用600ml庚烷洗涤,滤液在真空中浓缩成浅琥珀色油。取少量DCM中的粗品,装入50G卡式瓶(瑞典乌普萨拉)中,用100G卡式瓶和0-50%乙酸乙酯/DCM梯度洗脱。将馏分27-92合并并浓缩,得到17.59g(90%)的标题化合物(10),为1:1的端基差向异构体混合物。
1HNMR(400MHz,氯仿-d)δ6.02–5.88(m,1H)、5.09(dd,J=7.1,4.5MHz,4.5)、5.00–4.92(m,0.5H)、4.83(dd,J=9.3,4.7MHz,4.02–5.88(m,1H)、5.09(dd,J=7.1,4.5MHz,4.1,4.1,ddd,J=12.1,9,9.3,9.3,8.3,8.0MHz,8.0.0.5MHz,0.5H)、4.50(ddd,4.50(ddd,J=12.50(ddd,J=12.1,J=12.1,9,9,9,9.1,9,9,9.3,9,9,9.3,8.3,8.MHz,0.5H),2.88s,1H,2.11(m,3H)。
19F NMR(376MHz,氯仿-d)δ-188.81(dt,J=51.3,15.2Hz),-193.39(dd,J=50.9,12.2Hz)
(3S,4S,5R)-4-((叔丁基二苯基甲硅烷基)氧基)-5-((叔丁基二苯基甲硅烷基)氧基)甲基)-3-氟四氢噻吩-2-基乙酸酯(11)
制备:在氮气下,在1000mL单颈圆底瓶中,将(3S,4S,5R)-3-氟-4-羟基-5-(羟甲基)四氢噻吩-2-基乙酸酯(10)(11.85g,56.4mmol)溶解于DMF(180mL)中。用咪唑(9.59g,141mmol)处理溶液,然后用叔丁基二苯基氯硅烷(43.4mL,169mmol)处理,并且在室温下将反应混合物搅拌过夜。反应用1000ml乙酸乙酯稀释,用1×500ml 50%饱和氯化钠萃取,然后用3×150ml 50%饱和氯化钠萃取。有机层在无水硫酸镁上干燥,并在真空中浓缩成无色油。将粗品溶解在最低量的己烷中,装入340G UltraSil SNAP卡式瓶中,并在系统上用0-15%乙酸乙酯/己烷梯度洗脱成多个27mL馏分。将馏分27-66合并并浓缩,得到36.7g(95%无色油状标题化合物(11),为无色油。
1H NMR(400MHz,氯仿-d)δ7.78–7.68(m,4H),7.65–7.46(m,4H),7.46–7.20(m,12H),6.07–5.87(m,1H),5.15–4.86(m,1H),4.37–4.19(m,1H),3.81(qd,J=6.1,3.1Hz,0.4H),3.64(m,1H),3.41(m,1H),3.25(ddd,J=24.0,10.3,8.5Hz,1H),2.17(s,2H),1.88(s,1H),1.07(s,9H),0.94(s,9H).19F NMR(376MHz,氯仿-d)δ-184.98(dt,J=49.3,14.2Hz),-190.33–-190.64(m)
4-氨基-1-((2R,3S,4S,5R)-4-((叔丁基二苯基甲硅烷基)氧基)-5-(((叔丁基二苯基甲硅烷基)氧基)甲基)-3-氟四氢噻吩-2-基)-1,3,5-三嗪-2(1H)-酮(12)
制备:将HMD(21.97mL,105mmol)添加到氮杂胞嘧啶(2.91g,26.2mmol)和硫酸铵(0.115g,0.873mmol)中,并且将所得混合物在130℃下搅拌20h。减压去除多余的HMD,并且将剩余残余物悬浮在1,2-二氯乙烷(50mL)中。同时,将氢溴酸(醋酸中33%)添加至1,2-二氯乙烷(50mL)中的(3S,4S,5R)-4-((叔丁基二苯基甲硅烷基)氧基)-5-((叔丁基二苯基甲硅烷基)氧基)甲基)-3-氟四氢噻吩-2-基乙酸酯(11)(6g,8.73mmol),所得混合物在0℃下搅拌2h。添加75mL饱和碳酸氢钠使反应猝灭,并将混合物剧烈搅拌15min。分离各层并用无水硫酸镁干燥有机层。将中间溴溶液添加到单一份的硅烷化氮杂胞嘧啶悬浮液中,并将白色悬浮液加热至84℃。当反应到一定温度时,悬浮液变成了轻浆液。反应在84℃搅拌5小时。将反应物冷却至室温过夜,用75mL饱和碳酸氢钠稀释,并搅拌10分钟。所述浆液通过一层硅藻土过滤,并用新鲜的二氯甲烷清洗滤垫。将各层分离,将有机层在无水硫酸镁上干燥,并在真空中浓缩,得到5.3g米白色泡沫。将粗品溶解在最低量的二氯甲烷中,装入50GUltraSil SNAP卡式瓶中,并在系统上用10-65%乙酸乙酯/二氯甲烷梯度洗脱成多个27mL馏分。将馏分19-33合并并浓缩,得到2.7g(42%)白色泡沫。H-NMR表明材料为2:1β/α混合物。
将白色泡沫溶解于10mL无水乙醇(EtOH)中,并在室温下搅拌2h,同时细白色固体从混合物结晶出来。收集固体,用少量EtOH洗涤,并在过滤器上干燥,得到630mg(9%)纯C-1α端基异构体,为白色固体。真空浓缩母液,得到2.07克(32%)的标题化合物12,为白色泡沫(>20:1C-1β端基异构体)。该材料无需额外分馏即可使用。
质子,C-1α端基异构体:1H NMR(400MHz,氯仿-d)δ8.85(s,1H),7.53(ddd,J=14.6,8.0,4.2Hz,6H),7.48–7.25(m,14H),6.75(s,1H),6.10(dd,J=14.0,1.8Hz,1H),5.72(s,1H),5.09(dt,J=46.7,2.0Hz,1H),4.30(m,1H),3.97–3.88(m,1H),3.47(dd,J=10.2,6.6Hz,1H),3.43–3.33(m,1H),0.96(m,18H)
氟,C-1α端基异构体:19F NMR(376MHz,氯仿-d)δ-177.38(dt,J=46.8,12.5Hz)
质子,C-1β端基异构体:1H NMR(400MHz,氯仿-d)δ8.41(d,J=2.6Hz,1H),7.68–7.52(m,6H),7.57–7.42(m,4H),7.47–7.28(m,10H),7.04–6.99(m,1H),6.80(dd,J=24.5,3.6Hz,1H),5.69(s,1H),4.81(dt,J=50.8,2.8Hz,1H),4.47(m,1H),3.70–3.65(m,1H),3.60–3.44(m,2H),1.10(s,9H),0.89(s,9H)
氟,C-1β端基异构体:19F NMR(376MHz,氯仿-d)δ-194.16(ddd,J=50.5,24.6,7.4Hz)4-氨基-1-((2R,3S,4S,5R)-3-氟-4-羟基-5-(羟甲基)四氢噻吩-2-基)-1,3,5-三嗪-2(1H)-酮(1)
制备1:在氮气下,在200mL单颈圆底瓶中,将4-氨基-1-((2R,3S,4S,5R)-4-((叔丁基二苯基甲硅烷基)氧基)-5-(((叔丁基二苯基甲硅烷基)氧基)甲基)-3-氟四氢噻吩-2-基)-1,3,5-三嗪-2(1H)-酮(12)(5.9g,7.98mmol)溶解于四氢呋喃(45mL,555mmol)中。溶液用硅胶(21.16g,29.1mmol)上的四正丁基氟化铵处理,并在室温下搅拌1h。反应混合物用18g硅胶(230-400目)处理并浓缩至干燥。固体塞在50克卡式瓶上进行色谱分析,同时在系统上用0-12.5%(10%甲醇在IPA中)/二氯甲烷梯度(0-50%25%(10%甲醇在IPA中)/二氯甲烷极性相)洗脱成多个27mL馏分。将馏分33-84合并并浓缩得到1.83g糊状固体。用20mL乙腈研磨固体,通过过滤收集并在过滤器上干燥,得到1.48g(71%)标题化合物(1),为米白色固体。
1H NMR(400MHz,DMSO-d6)δ8.78(d,J=1.3Hz,1H),7.68–7.60(m,2H),6.29(dd,J=11.6,5.4Hz,1H),5.92(d,J=5.2Hz,1H),5.34(t,J=5.2Hz,1H),5.00(dt,J=50.7,5.8Hz,1H),4.27(m,1H),3.68(m,2H),3.23(q,J=5.5Hz,1H)ppm.13C NMR(101MHz,dmso)δ165.87,158.07,158.04,153.63,96.79,94.87,73.44,73.21,61.28,61.26,57.44,57.27,51.97,51.93.19F NMR(376MHz,DMSO-d6)δ-192.78(dt,J=50.6,11.7Hz)。熔点:208-209℃,d。燃烧分析:计算:C,36.64;H,4.23;F,7.24;N,21.36;S,12.22,发现:C,36.66;H,4.14;F,7.04;N,21.08;S,12.27.
制备2:在氮气下,在200mL单颈圆底瓶中,将4-氨基-1-((2R,3S,4S,5R)-4-((叔丁基二苯基甲硅烷基)氧基)-5-(((叔丁基二苯基甲硅烷基)氧基)甲基)-3-氟四氢噻吩-2-基)-1,3,5-三嗪-2(1H)-酮(12)(12.2g,16.51mmol)溶解于甲醇(无水)(110mL,16.51mmol)中。溶液用氟化铵(5.20g,140mmol)处理并在60℃下搅拌。在60℃下2h后的薄层色谱(30%MeOH/DCM)显示起始材料完全消耗。将混合物加热至60℃共3小时。将反应冷却至室温,与12g硅胶(230-400目)混合,并将混合物浓缩至干燥。在25G卡式瓶上用5-25%MeOH/DCM梯度洗脱粗塞为多个27mL馏分。将馏分12-66合并并浓缩,得到4.8g白色固体。用20mL无水乙醇研磨固体1h,收集白色固体,用甲醇洗涤,然后用乙醚洗涤,并在过滤器上干燥过夜,以提供2.40g(55%)标题化合物(1),为细白色固体。在真空中浓缩母液,得到2.05g白色泡沫,通过TLC和LCMS,该泡沫似乎主要含有标题化合物的分解产物。将残余物溶解在甲醇中,用10mL 吸附剂(60-100目,Sigma-Aldrich)处理,并浓缩至干燥。在25G 卡式瓶上对塞子进行色谱分析,用5-25%MeOH/DCM梯度洗脱成多个27mL馏分。将馏分15-22合并并浓缩,得到360mg白色泡沫。来自MeCN的泡沫结晶产生额外的264mg(6%)标题化合物(1),为细白色固体。
1H NMR(400MHz,DMSO-d6)δ8.74(d,J=1.3Hz,1H),7.64–7.57(m,2H),6.23(dd,J=11.5,5.4Hz,1H),5.89(d,J=5.2Hz,1H),5.31(t,J=5.2Hz,1H),4.96(dt,J=50.7,5.9Hz,1H),4.22(dq,J=11.5,5.7Hz,1H),3.71–3.55(m,2H),3.17(q,J=5.5Hz,1H).
13C NMR(101MHz,DMSO-d6)δ165.88,158.08,158.05,153.65,96.78,94.86,73.42,73.19,61.26,57.43,57.26,51.94,51.90ppm
19F NMR(376MHz,DMSO-d6)δ-192.77(dt,J=50.8,11.7Hz).
LC/MS:[M+H]=263.1,98.2%纯度
实施例2
NC160人肿瘤细胞系抗癌药物筛选
使用NC160人肿瘤细胞系抗癌药物筛选法(参见,例如,Shoemaker,NatureReviews Cancer2006,6:813-823;https://dtp.cancer.gov/discovery_development/nci-60/handling.htm)对所公开化合物的实施方案的抗癌活性进行筛选。
样本制备的标准操作程序
总述:分两部分进行NC160测试:首先,在10-5摩尔或15μg/ml的单一剂量下,在所有60个细胞系中测试单一浓度。如果所获得的结果符合选择标准,则在所有60个细胞系中以5x10倍稀释液再次测试化合物,最高剂量为10-4摩尔或150μg/ml。同时制备接受NCI60测试的化合物以用于1倍剂量和5倍剂量测试。
收到的试剂:已知分子量的合成物和纯化合物以及大分子和无分子量的化合物-对等分的识别用于测试的试剂进行称重,并转移到预先称重的玻璃瓶中。化合物溶解在这些小瓶中。除特别注明外,所有试剂均储存在-70℃的冷冻箱中。天然粗品-天然粗品提取物平铺在可拆卸的聚丙烯(PP)96孔微量滴定板上。干燥平板并存储在-20℃下,直到要求进行1倍剂量测试。根据1倍剂量测试的结果,选择进行5倍剂量测试的样品用标准试剂阿霉素NSC 123127柱从88孔重新排列至每96孔板72孔中,并创建和上传新的平板图以供分配。然后将提取物以40mg/ml的浓度溶解在二甲基亚砜或水中。
浓度要求-1倍剂量/体外癌症计划:二甲基亚砜:甘油9:1(除非另有说明),浓度为4mM的单次给药试验和40mM的5倍剂量试验。在这两种情况下,将溶液稀释1:400,分别得到10或100μM的高试验浓度。无分子量的合成剂(大分子)是在溶液中制备的二甲基亚砜:甘油9:1(除非另有说明),浓度为6和60mg/ml,稀释比例为1:400,试验浓度为15和150μg/ml。在二甲基亚砜中制备有机溶剂可溶的天然产物粗提取物,而通过水萃取产生的那些在水中溶解,均为40mg/ml。
体积要求-预筛/体外癌症计划:癌症筛查需要需要100μl用于1log、5倍剂量稀释的常规化合物,75μl用于1倍剂量测试。1倍剂量测试是在5倍剂量试验高浓度的十分之一下进行的,因此,对于分子量为40mM的化合物,体积要求为210μl+20%,对于无分子量(大分子)的化合物,体积要求为60000μg/ml=250μl时,体积要求为210μl+20%(即对于分子量=1000的化合物,体积要求小于10mg,对于重量/体积试验的化合物,体积要求小于15mg)。
化合物特殊说明:特殊说明(如氧敏感、光敏)可根据说明改变药剂的处理方式。
新鲜化合物:识别为在使用前需要新鲜制备的化合物在连续稀释前不超过1小时溶解。在TECAN Freedom 200(两种药物/板)上连续稀释,转移到柱板上,并在氮气下储存在干燥箱中,直至交付至测试实验室。
溶解标准操作程序
将信息输入NPSG TECAN系统:在开始溶解程序之前,将TECAN Freedom 200溶解的每种化合物的信息输入NPSG TECAN(Visual Basic instrument control and front endto ORACLE)系统中。一组72种化合物通过输入shiplist编号分配给一个瓶盘套(plateset)。发货单加载到TECAN软件中,该软件查找数量和分子量(从DIS Oracle表格中),并计算要添加到每个小瓶中的溶剂体积,以获得恒定浓度(40mM或60000μg/ml),如果材料不足,则调整浓度,进行一倍剂量测试和一次重新测试(75μl@4mM和200μl@40mM+20%或75μl@6,000μg/ml和200μl@60000μg/ml+20%)。通过ORADIS将用于预筛查的Platemap(定义哪个化合物在哪个孔中)上传到ORACLE PLATEWELL表中。
供应品和设备:按照PLATEMAP打印件上指定的发货单顺序,将小瓶放在TECAN桌上。TECAN Freedom机器人向每个小瓶中添加适当体积的溶剂(甲醇/乙酸乙酯/甲基-叔丁基醚,6:3:1),以获得恒定的浓度。技术人员单独检查每个小瓶,并对其进行超声波处理、加热等,以获得暴露时间保持在两小时以内的溶液。药物溶液转移前的培养板制备:技术人员制备三个96孔PP可分离培养板(一个用于1倍剂量测试,两个用于60细胞测试):向每个孔中添加100μl异丙醇中的10%甘油。在添加药物溶液和真空干燥后,每孔剩余10μL甘油。
TECAN将药液在小瓶中混合一次,然后将40μL(400μM)的药液转移到96孔可分离板的每个孔中进行1倍剂量测试,并将400μL(4000μM)药液转移到96孔PP可分离板中进行全60细胞筛选。所有板都被转移到SpeedVac系统进行干燥。所有溶剂在不加热的情况下通过高真空去除,在孔底留下甘油和药物的残留物。干燥板在-70℃下储存,直到要求进行测试,通常为1~3周。玻璃瓶中的未转移残留物在SpeedVac中干燥,并在-70℃下干燥储存,如果需要额外的重新测试,可以使用。
对于1倍剂量60细胞测试:在向组织培养基中的生长细胞添加药物的当天或前一天,将一条标准品(阿霉素,NSC 123127制备和储存与化合物相同)添加到可拆卸孔板中,并将90μl DMSO添加到每个孔(4mM溶液)中,并混合/超声处理并使用12通道手动移液器将75μl混合物转移到12通道储液板(柱板)上,该储液板密封并在氮气下储存在干燥箱中,直至交付至测试实验室。标签放置在储液板前部的左右两侧。它将是行中的第一个和最后一个NSC编号。行从可拆卸板转移到柱板的第3-12列。在加药前24小时内,将平板密封并储存在氮气中。
对于5倍剂量60细胞测试:在向组织培养基中的生长细胞添加药物的当天,向每个孔(40mM溶液)中添加90μl二甲基亚砜,并在TECAN Freedom 200的摇床上混合/超声处理。然后将试管放置在TECAN Freedom 200(两种药物/平板)上,并连续稀释/转移到柱板上,柱板密封并在氮气下储存于干燥箱中,直到交付给测试实验室。平板标签由SATO热转移打印机使用ORACLE前端程序选项AA-Expid NSC标签打印。标签分别放置在储液板前部的左右两侧,第一列一个药物,第12列2个药物。
运载体选择-合成:运载体的选择是二甲基亚砜和水。大多数试剂是用这两种运载体中的一种溶解的。应供应商要求或根据以往的试验方法使用其他运载体。使用挥发性溶剂作为运载体的试剂标记为“新鲜”,并在筛选添加后一小时内制备。目前,所有用于预筛选/癌症筛查的合成制剂都是在美国制备的二甲基亚砜:甘油9:1,除非表明是另一运载体。当表明是水时,化合物溶解于蒸馏水或不含血清的细胞培养基(RPMI 1640)中。所有需要四氢呋喃、乙醇、甲醇或其他挥发性溶剂的溶解剂都是新鲜制备的,以减少蒸发。
最小体积要求:溶解的目的是为筛选过程提供所需的最高浓度的试剂。但是,筛选试剂的程序所需的小瓶数量决定了可以添加的最小运载体的数目。如果材料量不足以产生所需数量的试样,则降低浓度以确保达到适当的体积。
体积要求-1倍剂量/体外癌症计划:癌症筛查需要100μl,1log,5倍剂量稀释常规化合物。对于溶解在TECAN上用于1倍剂量和5倍剂量癌症试验的化合物,需要250μl的最小体积,足以进行初始1倍剂量试验以及5倍剂量试验中的重新试验。
溶解度代码:试剂不会总是溶解到没有颗粒的透明溶液中。因此,通过最能描述试剂在运载体中的溶解度的代码来描述溶液。正在评估的是解决方案的清晰度。溶解度代码中不考虑是否存在颜色。
NC160筛选方法
NC160细胞一倍剂量筛选
总的描述:提交给NCI 60细胞筛选的所有化合物最初在整个NCI 60细胞面板中以单一高剂量(10-5M)进行测试。只有在最少数量的细胞系中满足预先确定的阈值抑制标准的化合物才能进行全5倍剂量分析。基于对历史DTP筛选数据的仔细分析,选择进入5倍剂量筛选的阈值抑制标准以有效捕获具有抗增殖活性的化合物。阈值标准可以随着附加数据变得可用而更新。
一倍剂量数据的解释:一倍剂量数据将作为处理细胞生长百分比的平均图报告,并且在外观上与5倍剂量分析的平均图相似。一倍剂量试验报告的数量相对于无药物对照以及相对于时间零点的细胞数量的生长。这允许检测生长抑制(值介于0和100之间)和致死率(值小于0)。这与下文所述的5倍剂量分析相同。例如,值100表示没有生长抑制。值为40意味着60%的生长抑制。值为0表示在实验过程中没有净增长。值为-40意味着40%的杀伤力。值为-100表示所有细胞都已死亡。一倍剂量平均图中的信息可用于COMPARE分析。
NC160细胞5倍剂量筛选:
在一倍剂量筛选中表现出显著生长抑制的化合物在五种浓度水平下对照60细胞组进行评估。
在含有5%胎牛血清和2mM L-谷氨酰胺的RPMI 1640培养基中生长癌症筛查组的人类肿瘤细胞系。对于一个典型的筛选实验,将细胞接种到100μL的96孔微量滴定板中,根据单个细胞系的倍增时间,铺板密度的范围为5,000个细胞/孔~40,000个细胞/孔。细胞接种后,在添加实验药物之前,将微量滴定板在37℃、5%CO2、95%空气和100%相对湿度下培养24小时。
24小时后,每个细胞系的两个平板用TCA原位固定,以表征在药物添加(Tz)时每个细胞系的细胞群的测量值。实验药物以所需最终最大试验浓度的400倍溶解在二甲亚砜中,并在使用前冷冻保存。添加药物时,解冻一份冷冻浓缩液,并用含有50μg/ml庆大霉素的完全培养基稀释至所需最终最大试验浓度的两倍。另外进行4倍、10倍或1/2log系列稀释,以提供总共5种药物浓度加上对照。将各份100μL这些不同药物稀释液添加到已经含有100μL培养基的适当微量滴定孔中,得到所需的最终药物浓度。
添加药物后,在37℃、5%CO2、95%空气和100%相对湿度的条件下将平板再培养48小时。对于贴壁细胞,通过添加冷TCA终止试验。通过温和添加50μL冷的50%(w/v)TCA(最终浓度,10%TCA)原位固定细胞,并在4℃下培养60分钟。丢弃上清液,用自来水冲洗平板五次并风干。向每个孔中加入存于1%乙酸中的0.4%(w/v)磺酰罗丹明B(SRB)溶液(100μL),并在室温下培养10分钟。染色后,用1%醋酸洗涤五次以除去未结合的染料,并风干平板。随后用10mM碱(Tris碱)溶解结合的染色剂,并在515nm波长的自动平板阅读器上读取吸光度。对于悬浮细胞,方法相同,区别是通过在孔底部固定沉淀细胞,轻轻添加50μL 80%TCA(最终浓度,16%TCA)终止测定。使用七个吸光度测量值[时间零点(Tz)、控制生长(C)和五个浓度水平(Ti)下药物存在下的测试生长],计算每个药物浓度水平下的生长百分比。生长抑制率计算如下:
[(Ti-Tz)/(C-Tz)]x100浓度,Ti>/=Tz
[(Ti-Tz)/Tz]x100浓度,Ti<Tz
根据[(Ti-Tz)/(C-Tz)]x100=50计算50%(GI50),这是导致对照细胞在药物培养期间蛋白质净增加(通过SRB染色测量)减少50%的药物浓度。导致总生长抑制(TGI)的药物浓度由Ti=Tz计算得出。表明治疗后细胞净损失的LC50(药物浓度导致药物治疗结束时测得的蛋白质比治疗开始时减少50%)由[(Ti Tz)/Tz]x100=-50计算得出。如果达到活性水平,则计算这三个参数中每个参数的值;但是,如果未达到或超过效果,则该参数的值表示为大于或小于测试的最大或最小浓度。
图3A-3B显示化合物1(4-氨基-1-((2R,3S,4S,5R)-3-氟-4-羟基-5-(羟甲基)四氢噻吩-2-基)-1,3,5-三嗪-2(1H)-酮)和5-氮杂-T-dCyd分别对白血病细胞系的GI50数据。图4A和4B分别显示化合物1和5-氮杂-T-dCyd对中枢神经系统(CNS)癌细胞系的GI50数据。图5A和5B分别显示化合物1和5-氮杂-T-dCyd对肾癌细胞系的GI50数据。图6A和6B分别显示化合物1和5-氮杂-T-dCyd对非小细胞肺癌细胞系的GI50数据。图7A和7B分别显示化合物1和5-氮杂-T-dCyd对黑色素瘤细胞系的GI50数据。图8A和8B分别显示化合物1和5-氮杂-T-dCyd对前列腺癌细胞系的GI50数据。图9A和9B分别显示化合物1和5-氮杂-T-dCyd对结肠癌细胞系的GI50数据。图10A和10B分别显示化合物1和5-氮杂-T-dCyd对卵巢癌细胞系的GI50数据。图11A和11B分别显示化合物1和5-氮杂-T-dCyd对乳腺癌细胞系的GI50数据。
实施例3
异种移植研究
在含有HCT-116人结肠癌细胞、BL0382人膀胱癌细胞、OVCAR3人卵巢癌细胞、NCI-H23NSCLC人肺癌细胞和HL-60人白血病细胞的小鼠中进行异种移植研究。使用RPMI 1640和10%胎牛血清和2mM l-谷氨酰胺,通过皮下注射体外生长的肿瘤细胞(HL-60、NCI-H23、OVCAR-3、HCT-116),在4-6周龄雌性裸鼠(nu/nu NCr)或NSG小鼠中产生人类肿瘤异种移植物。对于患者来源的异种移植(PDX)模型BL0382F1232,肿瘤片段从供体小鼠中连续传代,如其他异种移植模型所述(Plowman等人,“NCI药物开发中的人类肿瘤异种移植模型”,摘自:Teicher,B.A.(Ed.),《抗癌药物开发指南:临床前筛选、临床试验和批准》,Humana出版社,Totowa,NJ,第101-125页;1997年)。PDX供体肿瘤是将人源性肿瘤材料植入NSG小鼠体内制备的。所产生的肿瘤在NSG小鼠中连续传代,并将片段冷冻保存,以便随后从存档材料中建立新的肿瘤动物。将这些小鼠安置在AAALACi(国际实验动物护理评估和认证协会)认可的机构中,并随意提供食物和水。当肿瘤达到预定的起始重量(分期重量)时,将动物随机分为实验组并开始治疗。两组包括溶媒对照组和药物治疗组。根据先前的经验或其他地方所述的新进行的小鼠耐受性研究选择药物剂量(同上)。用双向卡尺测量肿瘤,计算肿瘤重量(mg)=(肿瘤长mm×肿瘤宽mm2)/2。使用StudyLog软件项目研究总监(StudyLog Systems,Inc.,加利福尼亚州南旧金山)进行数据收集和分析。
药物配比如下:
IP=腹腔内,IV=静脉内注射,PO=口服
*每个周期为一周。因此,“QDx5”周期包括两天的静置。
术后连续测量肿瘤体积和体重。结果如图12A和12B(HCT-116人结肠癌细胞)、图13A和13B(BL0382人膀胱癌细胞)、图14A和14B(OVCAR3人卵巢癌细胞)、图15A和15B(NCI-H23非小细胞肺癌人肺癌细胞)、图16A和16B(HL-60人白血病细胞)所示。
实施例4
用卤化5-氮杂-T-dCyd类似物进行处理
确定患有或疑似患有可使用卤化5-氮杂-T-dCyd类似物治疗的疾病的个体。该疾病可以是一种至少部分以存在肿瘤细胞为特征的疾病。在一些情况下,该疾病是癌症。可基于临床表现和/或通过执行证明存在疾病(如癌症)的试验来选择个体,所述疾病至少部分地以存在肿瘤细胞为特征。在一些示例中,个体患有实体瘤或血癌。
通过以临床医生确定的治疗有效量施用卤化5-氮杂-T-dCyd类似物或其立体异构体、互变异构体或医药上可接受的盐来治疗个体。在一些示例中,该化合物为4-氨基-1-((2R,3S,4S,5R)-3-氟-4-羟基-5-(羟甲基)四氢噻吩-2-基)-1,3,5-三嗪-2(1H)-酮。通过任意合适的方式,如肠胃外(例如,静脉内、动脉内、皮下、肌肉内)或鞘内注射或通过口服来施用该化合物。可以通过常规手段来评估治疗效果,例如,预防肿瘤生长、减少肿瘤生长、减少或缺乏转移、血细胞计数正常化等。在一些示例中,通过计算机断层扫描(CT)、磁共振成像(MRI)或正电子发射断层扫描(PET)进行评估。
治疗有效量的第二活性剂可与所述化合物共同施用。所述化合物和第二活性剂可在单一组合物中单独地或一起施用。第二活性剂可以通过相同的途径或不同的途径施用。如果同时施用,则所述化合物和第二活性剂可组合在单一药物组合物中或可作为两种药物组合物同时施用。第二活性剂可以是例如抗癌剂、抗炎剂、抗菌剂、抗病毒剂、麻醉剂等。
鉴于可以应用所公开的发明的原理的许多可能的实施例,应当认识到,所示的实施例仅仅是本发明的优选示例,并且不应当被视为限制本发明的范围。相反,本发明的范围由以下权利要求限定。因此,我们将所有在这些权利要求的范围和精神内的东西都称为我们的发明。
Claims (20)
2.根据权利要求1所述的化合物,其中:
(i)X为F;或
(ii)Y为氢或F;或
(iii)每个R为氢;或
(iv)Ra为氢;或
(v)上述(i)、(ii)、(iii)和(iv)的任意组合。
7.一种药物组合物,其包含根据权利要求1~6中任意一项所述的化合物和药学上可接受的载体。
8.根据权利要求7所述的药物组合物,其中所述药物组合物被配制用于静脉给药、口服给药、腹腔给药、皮下给药、直肠给药或含服给药。
9.一种抑制瘤形成的方法,包括:
使瘤形成细胞与有效量的根据权利要求1至6中任意一项所述的化合物接触。
10.根据权利要求9所述的方法,其中使瘤形成细胞与所述有效量的化合物接触减少瘤形成细胞的增殖。
12.根据权利要求9~11中任意一项所述的方法,其中使瘤形成细胞与所述有效量的化合物接触包括向患有或疑似患有至少部分以存在瘤形成细胞为特征的疾病的个体施用治疗有效量的化合物。
13.根据权利要求12所述的方法,其中所述疾病为癌症。
14.根据权利要求13所述的方法,其中所述癌症为肾癌、膀胱癌、乳腺癌、结肠癌、子宫内膜癌、皮肤癌、血液癌、胰腺癌、前列腺癌、骨癌、肝癌、肺癌、食管癌或中枢神经系统癌。
15.根据权利要求12~14中任意一项所述的方法,其中向所述个体施用所述治疗有效量的化合物减少所述疾病的病症或症状。
16.根据权利要求15所述的方法,其中:
所述疾病的病症或症状为实体瘤,并且向所述个体施用所述治疗有效量的化合物减少所述实体瘤的生长,减小所述实体瘤的体积,减少所述实体瘤的转移或其任意组合;或者
所述疾病的病症或症状为全血计数异常,并且向所述个体施用所述治疗有效量的化合物至少部分地使全血计数正常化。
17.根据权利要求12~16中任意一项所述的方法,其中施用所述治疗有效量的化合物包括向所述个体施用包含所述治疗有效量的化合物的药物组合物。
18.根据权利要求12~17中任意一项所述的方法,其中施用包括静脉给药、口服给药、腹腔给药、皮下给药、直肠给药或含服给药。
19.根据权利要求12~18中任意一项所述的方法,进一步包括向所述个体施用第二活性剂。
20.根据权利要求19所述的方法,其中所述第二活性剂为抗癌剂、抗炎剂、抗菌剂、抗病毒剂、麻醉剂或其任意组合。
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